BET bromodomain protein inhibition is a therapeutic option for medulloblastoma

Medulloblastoma is the most common malignant brain tumor of childhood, and represents a significant clinical challenge in pediatric oncology, since overall survival currently remains under 70%. Patients with tumors overexpressing MYC or harboring a MYC oncogene amplification have an extremely poor prognosis. Pharmacologically inhibiting MYC expression may, thus, have clinical utility given its pathogenetic role in medulloblastoma. Recent studies using the selective small molecule BET inhibitor, JQ1, have identified BET bromodomain proteins, especially BRD4, as epigenetic regulatory factors for MYC and its targets. Targeting MYC expression by BET inhibition resulted in antitumoral effects in various cancers. Our aim here was to evaluate the efficacy of JQ1 against preclinical models for high-risk MYC-driven medulloblastoma. Treatment of medulloblastoma cell lines with JQ1 significantly reduced cell proliferation and preferentially induced apoptosis in cells expressing high levels of MYC. JQ1 treatment of medulloblastoma cell lines downregulated MYC expression and resulted in a transcriptional deregulation of MYC targets, and also significantly altered expression of genes involved in cell cycle progression and p53 signalling. JQ1 treatment prolonged the survival of mice harboring medulloblastoma xenografts and reduced the tumor burden in these mice. Our preclinical data provide evidence to pursue testing BET inhibitors, such as JQ1, as molecular targeted therapeutic options for patients with high-risk medulloblastomas overexpressing MYC or harboring MYC amplifications

Airway remodeling: The Drosophila model permits a purely epithelial perspective

Airway remodeling is an umbrella term for structural changes in the conducting airways that occur in chronic inflammatory lung diseases such as asthma or chronic obstructive pulmonary disease (COPD). The pathobiology of remodeling involves multiple mesenchymal and lymphoid cell types and finally leads to a variety of hardly reversible changes such as hyperplasia of goblet cells, thickening of the reticular basement membrane, deposition of collagen, peribronchial fibrosis, angiogenesis and hyperplasia of bronchial smooth muscle cells. In order to develop solutions for prevention or innovative therapies, these complex processes must be understood in detail which requires their deconstruction into individual building blocks. In the present manuscript we therefore focus on the role of the airway epithelium and introduce Drosophila melanogaster as a model. The simple architecture of the flies’ airways as well as the lack of adaptive immunity allows to focus exclusively on the importance of the epithelium for the remodeling processes. We will review and discuss genetic and environmentally induced changes in epithelial structures and molecular responses and propose an integrated framework of research for the future

Influence of Honey on the Suppression of Human Low Density Lipoprotein (LDL) Peroxidation (In vitro)

The antioxidant activity of four honey samples from different floral sources (Acacia, Coriander, Sider and Palm) were evaluated with three different assays; DPPH free radical scavenging assay, superoxide anion generated in xanthine–xanthine oxidase (XOD) system and low density lipoprotein (LDL) peroxidation assay. The dark Palm and Sider honeys had the highest antioxidant activity in the DPPH assay. But all the honey samples exhibited more or less the same highly significant antioxidant activity within the concentration of 1mg honey/1 ml in XOD system and LDL peroxidation assays. The chemical composition of these samples was investigated by GC/MS and HPLC analysis, 11 compounds being new to honey. The GC/MS revealed the presence of 90 compounds, mainly aliphatic acids (37 compounds), which represent 54.73, 8.72, 22.87 and 64.10% and phenolic acids (15 compound) 2.3, 1.02, 2.07 and 11.68% for Acacia, Coriander, Sider and Palm honeys. In HPLC analysis, 19 flavonoids were identified. Coriander and Sider honeys were characterized by the presence of large amounts of flavonoids

Customer active power consumption prediction for the next day based on historical profile

Energy consumption prediction application is one of the most important fieldsthat is artificially controlled with Artificial Intelligence technologies to maintainaccuracy for electricity market costs reduction. This work presents a way to buildand apply a model to each costumer in residential buildings. This model is built by using Long Short Term Memory (LSTM) networks to address a demonstration of time-series prediction problem and Deep Learning to take into consideration the historical consumption of customers and hourly load profiles in order to predict future consumption. Using this model, the most probable sequence of a certain industrial customer’s consumption levels for a coming day is predicted. In the case of residential customers, determining the particular period of the prediction in terms of either a year or a month would be helpful and more accurate due to changes in consumption according to the changes in temperature and weather conditions in general. Both of them are used together in this research work to make a wide or narrow prediction window.A test data set for a set of customers is used. Consumption readings for anycustomer in the test data set applying LSTM model are varying between minimum and maximum values of active power consumption. These values are always alternating during the day according to customer consumption behavior. This consumption variation leads to leveling all readings to be determined in a finite set and deterministic values. These levels could be then used in building the prediction model. Levels of consumption’s are modeling states in the transition matrix. Twenty five readings are recorded per day on each hour and cover leap years extra ones. Emission matrix is built using twenty five values numbered from one to twenty five and represent the observations. Calculating probabilities of being in each level (node) is also covered. Logistic Regression Algorithm is used to determine the most probable nodes for the next 25 hours in case of residential or industrial customers.Index Terms—Smart Grids, Load Forecasting, Consumption Prediction, Long Short Term Memory (LSTM), Logistic Regression Algorithm, Load Profile, Electrical Consumption.</p

A homozygous loss-of-function mutation in PTPN14 causes a syndrome of bilateral choanal atresia and early infantile-onset lymphedema

A homozygous truncating mutation in nonreceptor tyrosine phosphatase 14 (PTPN14) has recently been associated with an extremely rare autosomal recessive syndrome of congenital posterior choanal atresia and childhood-onset lymphedema. PTPN14 has been shown to interact directly with the vascular endothelial growth factor receptor 3 (VEGFR3), a receptor tyrosine kinase essential for lymphangiogenesis. Here we present an Iranian family with a single child affected by high-arched palate, congenital hypothyroidism, dysmorphic face, bilateral choanal atresia and infantile-onset lymphedema. Screening of the PTPN14 revealed a novel homozygous frameshift mutation in exon 4 predicted to result in premature truncation of the polypeptide product, which segregated with the disease phenotype. To our knowledge, this is the second family with “choanal atresia and lymphedema syndrome” to be reported worldwide. In contrast to the first reported family that showed lymphedema in late childhood, the patient described here displays lymphedema in her lower limbs at early infancy associated with growth delay, mild facial swelling, congenital hypothyroidism and some minor developmental abnormalities. This report confirms the causality of PTPN14 loss-of-function mutations and further expands the clinical phenotype of this rare genetic syndrome

Smart Electric Grids Three-Phase Automatic Load Balancing Applications using Genetic Algorithms

Smart power grid is going to be the future grid. Conventional, renewable and alternate sources incorporating for power generation[1]. Smart Electrical Grids require nowadays a large interest in the electrical load distribution balancing problem.  This problem is a well known for not having an optimal solution for large-scale systems, where the number of single phase consumers connected to three phase systems increases especially in very large-scale electrical distribution systems.  This paper presents a new control technique for an automatic circuit phase change as well as an optimisation approach using Genetic Algorithms (GA) used to enhance the solution of electrical load distribution balancing problem.  In the first part of the paper, the system under study is introduced, as well as the various solutions adopted.  In the second part of the paper, a GA formulation and implementation of the solution is presented.  The efficiency of the GA solution is also discussed

Interpreting Soft Sediment Deformation and Mass Transport Deposits as Seismites in the Dead Sea Depocenter

Peer reviewedPublisher PD

Comparison and Outcome Analysis of Patients with Takotsubo Cardiomyopathy Triggered by Emotional Stress or Physical Stress

Background: Previous studies revealed that takotsubo cardiomyopathy (TTC) is triggered by physical and emotional stresses. This study was performed to determine the short- and long-term prognostic impact of emotional- and physical stress associated with TTC.Methods and results: Our institutional database constituted a collective of 84 patients diagnosed with TTC between 2003 and 2015. The patients were divided into two groups as per the presence of emotional stress (n = 24, 21%) or physical stress (n = 60, 52.6%). The endpoint was a composite of in-hospital events (thromboembolic events and life-threatening arrhythmias), myocardial infarction, all-cause of mortality, re-hospitalization due to heart failure, stroke, and recurrence of TTC. A Kaplan–Meier analysis indicated a significantly lower event-free survival rate over a mean follow-up of 5 years in the emotional group than the physical stress group (log-rank, p &lt; 0.01). Multivariate Cox regression analysis revealed only emotional stress (HR 0.4, 95% CI: 0.2–0.9, p &lt; 0.05) as a negative independent predictor of the primary endpoint.Conclusion: Rates of in-hospital events and short- as well as long-term events were significantly lower in TTC patients suffering from emotional stress as compared to patients with physical stress

Comparison of high-order curved finite elements

Several finite element techniques used in domains with curved boundaries are discussed and compared, with particular emphasis in two issues: the exact boundary representation of the domain and the consistency of the approximation. The influence of the number of integration points on the accuracy of the computation is also studied. Two-dimensional numerical examples, solved with continuous and discontinuous Galerkin formulations, are used to test and compare all these methodologies. In every example shown, the recently proposed NURBS-enhanced finite element method (NEFEM) provides the maximum accuracy for a given spatial discretization, at least one order of magnitude more accurate than classical isoparametric finite element method (FEM). Moreover, NEFEM outperforms Cartesian FEM and p-FEM, stressing the importance of the geometrical model as well as the relevance of a consistent approximation in finite element simulations.Peer ReviewedPostprint (published version

Characterization and Tuning of Ultra High Gradient Permanent Magnet Quadrupoles

The application of quadrupole-devices with high field gradients and small apertures requires precise control over higher order multipole field components. We present a new scheme for performance control and tuning, which allows the illumination of most of the quadrupole-device aperture because of the reduction of higher order field components. Consequently, the size of the aperture can be minimized to match the beam size achieving field gradients of up to 500 T/m at good imaging quality. The characterization method based on a Hall probe measurement and a Fourier analysis was confirmed using the high quality electron beam at the Mainz Microtron MAMI